1. Field of the Invention
The present invention relates generally to the fields of virology, immunology, disease treatment and prevention. More particularly, it concerns azido-diarylpyrimidines and their use in inactivating reverse transcriptase. Methods of inactivation of viruses and microbes are useful for preventing disease through decreasing the risk of infection associated with exposure to viruses and microbes such as it is the case with the family of retroviruses of which HIV is a member.
2. Description of Related Art
The HIV viruses are members of the Retroviridae family and, more particularly, are classified within the Lentivirinae subfamily. Like nearly all other viruses, the replication cycles of members of the Retroviridae family, commonly known as the retroviruses, include attachment to specific cell receptors, entry into cells, synthesis of proteins and nucleic acids, assembly of progeny virus particles (virions), and release of progeny viruses from the cells. A unique aspect of retrovirus replication is the conversion of the single-stranded RNA genome into a double-stranded DNA molecule that must integrate into the genome of the host cell prior to the synthesis of viral proteins and nucleic acids.
Retrovirus virions are enveloped and contain two copies of the genome. The conversion of the genomic RNA into DNA is provided by the viral protein reverse transcriptase (RT). This protein is bound to the RNA genome within the virion, and its enzymatic conversion of the genome to DNA in many instances start prior to viral entry into the host cell and is completed after viral entry. The initiation of the conversion process may initiate in the virion particles themselves, is known as endogenous reverse transcription (ERT). ERT may be important in increasing the infectivity of HIV in sexual transmission (Zhang et al., 1993, 1996).
Because of the requirement for reverse transcription in the viral replication cycle, compounds that interfere with RT activity have been utilized as anti-HIV therapeutic agents. Many of these compounds, including 3′-azido-2′,3′-dideoxythymidine (AZT), are nucleoside analogs that, upon activation by host cell kinases, are competitive inhibitors of reverse transcriptase (Furman et al., 1986). Other anti-RT compounds are nonnucleoside inhibitors (NNI or NNRTI), hydrophobic compounds that do not require cellular modification for antiviral activity. Examples of such compounds include nevirapine (Grob et al., 1992; Merluzzi et al., 1990), the pyridinones (Carroll et al., 1993; Goldman et al., 1991), and the carboxanilides (Bader et al., 1991; Balzarini et al., 1995, 1996). The nevirapine analog 9-azido-5,6-dihydro-11-ethyl-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one (9-AN) and the carboxanilide analog N-[4-chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furanocarbothiamide (UC781™) have been shown to be potent inhibitors of RT. Compounds, including azido-labeled compounds, for the photoinactivation of reverse transcriptase are disclosed in U.S. Pat. Nos. 6,653,130; 6,649,410; 6,503,753; and 6,383,806, each of which is incorporated herein by reference.
A series of anti-HIV candidate DAPY analogues were published by Ludovici (Ludovici et al., 2001), which is incorporated herein by reference. DAPY compounds, such as dapivirine and etravirine, have shown great potency in inhibiting the activity of HIV reverse transcriptase. While these are capable of binding reverse transcriptase, the binding is reversible. Thus, eventually the reverse transcriptase can escape inactivation by the DAPY compound. Accordingly, there is a need for compounds and methods that can permanently inactivate reverse transcriptase activity.